Breakthroughs in migraine treatment

A recently published thematic series in The Journal of Headache and Pain explores the most important aspects of a small molecule associated with migraine: Pituitary adenylate cyclase activating peptide (PACAP). The thematic series covers everything about PACAP from its discovery in the central nervous system to experimental studies with relevance to primary headaches. To find out more, we invited migraine researcher Song Guo to tell us the latest breakthroughs in migraine treatment.

Migraine is the most common neurological disorder, afflicting 10-15% of adults worldwide. Because migraines rank amongst the most debilitating conditions, the annual cost and public health burden are substantial.

Migraines are characterized primarily as attacks of severe headache accompanied by symptoms such as nausea, vomiting, and discomfort caused by sound or light. They can be episodic or chronic which is defined as having headache less or more than 15 days per month.

Despite better understanding of the underlying mechanisms of migraine, significant gaps remain in the identification of signaling pathways and specific biomarkers. Nevertheless, a likely breakthrough in treatment options seems to be in the horizon.

Human model of migraine

For the last 9 years I have done research at the Danish Headache Center (DHC) in Copenhagen, Denmark, an institution that has for more than 30 years been a world leader in the research of migraine mechanisms. A central part of this endeavor is the use of the experimental human migraine model, where disease mechanisms are dissected by experimentally inducing migraine attacks in humans.

These studies have established that neurotransmitters such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) can trigger migraine attacks associated with dilation of blood vessels in the brain. In this context, PACAP38 has emerged as a key signaling molecule implicated in migraine and possibly also in cluster headache. Moreover, findings from brain imaging studies have demonstrated neuronal and vascular changes in migraine patients after PACAP38 infusion.

A novel migraine-specific drug target

PACAP38 has emerged as a key signaling molecule implicated in migraine and possibly also in cluster headache.

PACAP38 is a powerful vasodilator and potent trigger of migraine attacks. It belongs to the glucagon/secretin superfamily of peptides together with vasoactive intestinal polypeptide (VIP). Both of these peptides activate VPAC1 and VPAC2 receptors equally, but only PACAP38 activates the PAC1 receptor.

However, very interestingly, VIP induces vasodilation but does not induce migraine attacks in humans. It is therefore likely that the migraine-provoking activity of PACAP38 is caused by the PAC1 receptor activation. For that reason it is possible that an antagonist selective for the PAC1 receptor could be effective in the treatment of migraine.

New era in migraine treatment with antibodies

Recently, targeting the calcitonin gene-related peptide (CGRP) pathway to treat migraine is the first mechanism based and focused therapeutic option to date that is shown to be effective. Clinical data from phase II and III trials of four CGRP function-blocking monoclonal antibodies (mAbs) – antibodies made of identical immune cells – collectively show a positive effect in the preventive treatment of episodic and chronic migraine with favorable side effect profiles. The anti-CGRP mAbs are expected to act in the nervous system structures outside the blood-brain barrier but their exact site of action is yet unclear and further studies are warranted.

In view of this, it would be very interesting to see the effect of anti-PAC1 receptor mAbs in migraine patients.

In my opinion, the anti-PAC1 receptor mAbs have the potential to be more effective than anti-CGRP mAbs due to the fact that the PAC1 target is seemingly more migraine-specific. I am therefore eagerly awaiting the results of an ongoing proof of concept randomized clinical trial revealing the therapeutic potential of anti-PAC1 receptor antibodies for migraine prevention. Whether this will be another breakthrough and paradigm change in the treatment of migraine, only time will tell.

One Comment

I’m anxious to read more about your developments and research findings regarding the causes and treatments for migraines. Please know that you are appreciated for your interest in research of migraine disease.
I had my first migraine as a child. I remember throwing up after school, going to bed, sleeping all night, then feeling better the next morning.
I’ve suffered with migraines caused by certain triggers (monthly, hunger, too much sun, not enough sleep) since I was a teenager.
Chronic migraines developed after age 27 (childbirth in 1978). Headaches disappeared around third month of pregnancy, then returned with a vengeance after childbirth. They’ve gotten increasingly worse over the years. Hormonal migraines have lessened but migraine triggers have worsened.
I’ve tried so many preventative medications. Triptans are a ‘must have’ which helps but doesnt always work. After 50 years of suffering and searching, this gives me new hope for some life for my remaining years. (I’m 66)
Thank you for your work, expertise, and time well spent on this disabling and misunderstood disease. It’s a disease that’s been neglected far too long. Many valuable lives have been wasted and lost suffering with this illness. Maybe the saddest part of all is that few people, even those closest to the ones suffering, understand those who suffer.
Carolyn

Song Guo is a medical doctor from the Danish Headache Center in Copenhagen. His main area of research is human models of migraine. He has always had a strong fascination of the brain and has been doing migraine research for the last 9 years.